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PURPOSE: Endoscopic surgery is widely accepted for both elective and emergent abdominal surgery. This study was performed to assess the accuracy of preoperative adhesion mapping by abdominal ultrasonography (US). METHODS: Intra-abdominal intestinal adhesions on the abdominal wall in 50 patients with a history of abdominal surgery were prospectively assessed by the visceral slide test with US before laparoscopic surgery from 2019 to 2022. Adhesion was assessed in six separate abdominal zones during US. Actual adhesion on the abdominal wall was confirmed during laparoscopic surgery. RESULTS: The sliding distances in upper right, upper central, upper left, lower right, lower central, and lower left zones in patients with versus without intestinal adhesion were 4.4 versus 1.4 cm (P = .004), 3.4 versus 2.5 cm, 4.3 versus 1.3 cm (P = .011), 3.1 versus 1.5 cm (P = .0014), 3.3 versus 1.1 cm (P = .013), and 3.4 versus 0.8 cm (P = .0061), respectively. Receiver operating characteristic analysis revealed the optimal value of sliding distance as 2.5 cm and the area under the curve as 0.86. The specificity of US assessment of adhesion was lower in the central zone than in lateral zones. Loose adhesion mostly seen around the scar was attributed to either filmy tissue or omental adhesion, leading to visceral sliding during US. CONCLUSION: This study revealed the reason for insufficient accuracy of preoperative US assessment of intestinal adhesion around the scar area because of loose adhesion. The upper lateral area might be optimal for first port insertion.
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Laparoscopía , Ultrasonografía , Humanos , Adherencias Tisulares/diagnóstico por imagen , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Adulto , Cuidados Preoperatorios/métodos , Pared Abdominal/diagnóstico por imagen , Pared Abdominal/cirugíaRESUMEN
BACKGROUND/AIM: Genomic examination of tumor tissue has been clinically accepted, and the identification of actionable mutations for molecular-targeted therapy may provide substantial survival benefit for patients with advanced malignancies. CASE REPORT: A female patient in her 60s showed a stenosis of the afferent loop of the small intestine because of circumferential metastatic tumor 14 months after curative surgery for hilar cholangiocarcinoma. Chemotherapy with gemcitabine plus cisplatin was administered for 18 months. An oncopanel examination was performed during chemotherapy, and a high tumor mutation burden was revealed. At 38 months after surgery, a new recurrent tumor, 2.7 cm in size, was observed in the abdominal wall, which was histologically proven to be metastatic adenocarcinoma. Atezolizumab was administered. After three cycles of treatment, treatment was switched to pembrolizumab because of its acceptance by healthcare insurance. The recurrent tumors in the abdominal wall and small intestine disappeared 6 months after the administration of immune checkpoint inhibitor, and the patient has continued pembrolizumab, surviving for 76 months after surgery without any clinical evidence of tumor. CONCLUSION: Immune checkpoint blockade successfully prolonged the survival of a patient with advanced hilar cholangiocarcinoma with high tumor mutation burden, although the optimal number of mutations for such a successful response needs to be clarified.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Inhibidores de Puntos de Control Inmunológico , Mutación , Humanos , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/cirugía , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: Neutrophil-to-lymphocyte ratio (NLR) is a prognostic indicator for several malignancies, including pancreatic cancer. We developed a novel combined NLR score (cNLRS) based on baseline NLR and change in NLR after chemotherapy (ΔNLR), and examined its prognostic value and role in chemotherapeutic response in patients with advanced pancreatic cancer. PATIENTS AND METHODS: This study retrospectively assessed 210 advanced pancreatic cancer patients receiving chemotherapy between 2010 and 2021. The cNLRS was developed and its association with chemotherapeutic response and prognosis was investigated. RESULTS: The cNLRS consisted of baseline NLR ≥2.5 and ΔNLR ≥0, both of which were remained as independent poor predictors of prognosis adjusting for other traditional clinicopathological features. A high cNLRS served as an independent prognostic factor of reduced overall survival. Of note, the cNLRS was significantly associated with disease control rate and treatment duration not only in 1st line treatment but also in 2nd line treatment. CONCLUSION: The cNLRS established as a useful prognostic biomarker might be associated with chemotherapeutic response and could predict survival in advanced patients with pancreatic ductal adenocarcinoma treated with chemotherapy.
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Neutrófilos , Neoplasias Pancreáticas , Humanos , Neutrófilos/patología , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pronóstico , Linfocitos/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patologíaRESUMEN
Comprehensive genomic profiling (CGP) of a metastatic liver tumor biopsy specimen suggested that the patient, who was initially diagnosed with cholangiocarcinoma, had colorectal cancer. The identification of both FBXW7 and APC mutations is deemed characteristic of colorectal cancer. Indeed, subsequent colonoscopy revealed sigmoid colon carcinoma that led to tumor resection followed by systemic chemotherapy. CGP is principally used to identify agents that might potentially benefit the patient. However, results must be interpreted carefully to ensure consistency with the initial diagnosis.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Mutación , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Colorrectales/genética , Genómica/métodosRESUMEN
Although laparoscopic cholecystectomy is a well-established surgical procedure, an accessory hepatic duct (AcHD) entering the cystic duct is poorly understood. A 77-year-old woman with symptomatic cholecystlithiasis was referred to our hospital. Abdominal ultrasonography indicated several small stones in the gall bladder. Magnetic resonance cholangiopancreatography (MRCP) did not reveal an anomalous cystic duct. Dissecting the gall bladder bed at operation, AcHD entering the cystic duct was suspected. Intraoperative cholangiography revealed that B5 branch entered the cystic duct. We ligated the AcHD, and divided it. Laparoscopic cholecystectomy was completed, and the patient was discharged without any complication. A week after the operation, MRCP showed that ventral branch of B5 was dilated. The patient showed no symptom for more than a year. The present case exhibited extremely rare AcHD entering the cystic duct, which was hardly recognized before surgery. It is possible to recognize such anomalous variants with standard laparoscopic approach based on 2018 Tokyo Guidelines and with attention to the possibilities of AcHD entering the cystic duct.
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Colecistectomía Laparoscópica , Colecistolitiasis , Femenino , Humanos , Anciano , Conducto Cístico/cirugía , Colecistectomía Laparoscópica/métodos , Colecistolitiasis/complicaciones , Colecistolitiasis/cirugía , Conducto Hepático Común/cirugía , ColangiografíaRESUMEN
A man in his 70s with a 10 cm abdominal mass in the tail of the pancreas was diagnosed with pancreatic tail cancer. Distal pancreatectomy with curative intent was performed. Since tumour invasion of the spleen and transverse colon was suspected, pancreatectomy with splenectomy, left adrenalectomy and partial transverse colectomy was performed. Pathological examination of the resected specimen showed a giant pancreatic tumour, and a diagnosis of locally invasive solid pseudopapillary neoplasm (SPN) of the pancreas was made. The patient achieved 8-year survival without any recurrences. We herein report a very rare case of a giant pancreatic SPN with splenic infiltration and lymph node metastasis that was cured by resection.
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Neoplasias Glandulares y Epiteliales , Neoplasias Pancreáticas , Masculino , Humanos , Bazo/patología , Metástasis Linfática , Páncreas/patología , Pancreatectomía , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/cirugía , Neoplasias Glandulares y Epiteliales/cirugía , Sobrevivientes , Neoplasias PancreáticasRESUMEN
BACKGROUND: Postoperative pancreatic fistula (POPF) is a critical complication of pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC). Recent papers reported that serum carbohydrate antigen (CA)19-9 levels predicted long-term prognosis. We investigated whether preoperative serum CA19-9 levels were associated with POPF in PDAC patients. METHODS: This cohort study was conducted at a single institution retrospectively. Clinicopathologic features were determined using medical records. RESULTS: Among of 196 consecutive patients who underwent pancreatectomy against PDAC, 180 patients whose CA19-9 levels were above the measurement sensitivity, were registered in this study. The patients consisted of 122 patients who underwent pancreaticoduodenectomy and 58 patients who underwent distal pancreatectomy. Several clinicopathological factors, including CA 19-9 level, as well as surgical factors were determined retrospectively based on the medical records. Patients with high CA19-9 levels had a significantly higher incidence of POPF than those with low levels (43.9 vs. 13.0%, P < 0.0001). The receiver operating characteristic curves calculated that the cutoff CA19-9 value to predict POPF was 428 U/mL. CA19-9, BMI, curability, and histology were statistically significant risk factors for POPF by univariate analysis. Multivariate analysis showed that CA19-9 and BMI levels were statistically significant independent risk factors for POPF. CA19-9 levels were correlated with both histology and curability. Disease free survival and overall survival of patients with higher levels of CA19-9 were significantly shorter than that of patients with lower levels of preoperative serum CA19-9. CONCLUSIONS: In patients undergoing pancreatectomy for PDAC, higher preoperative CA19-9 levels are a significant predictor for POPF.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Fístula Pancreática/diagnóstico , Fístula Pancreática/etiología , Fístula Pancreática/cirugía , Antígeno CA-19-9 , Estudios Retrospectivos , Estudios de Cohortes , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Pancreaticoduodenectomía/efectos adversos , Pancreatectomía/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Neoplasias PancreáticasRESUMEN
BACKGROUND: Laparoscopic cholecystectomy is a well-established surgical procedure and is one of the most commonly performed gastroenterological surgeries. Therefore, strategy for the management of rare anomalous cystic ducts should be determined. CASE PRESENTATION: A 56-year-old woman was admitted to our hospital owing to upper abdominal pain and diagnosed with acute cholecystitis. Magnetic resonance cholangiopancreatography suspected that several small stones in gallbladder and the right hepatic duct drained into the cystic duct. Endoscopic retrograde cholangiopancreatography confirmed the cystic duct anomaly, and an endoscopic nasobiliary drainage catheter (ENBD) was placed at the right hepatic duct preoperatively. Intraoperative cholangiography with ENBD confirmed the place of division in the gallbladder, and laparoscopic subtotal cholecystectomy was safely performed. CONCLUSIONS: The present case exhibited rare right hepatic duct anomaly draining into the cystic duct, which might have caused biliary tract disorientation and bile duct injury (BDI) intraoperatively. Any surgical technique without awareness of this anomaly preoperatively might insufficiently prevent BDI, and preoperative ENBD would facilitate safe and successful surgery.
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PURPOSE: The pharmacokinetics (PKs) of cisplatin have not been investigated in patients with renal dysfunction, characterized by creatinine clearance (Ccr) < 60 mL/min. In this study, we performed a population pharmacokinetic (PPK) analysis of unchanged cisplatin in patients with renal dysfunction. We investigated the effects of renal dysfunction on the PKs and nephrotoxicity of unchanged cisplatin. METHODS: We enrolled 23 patients with moderate renal dysfunction (Ccr calculated to be 30-60 mL/min using the Cockcroft-Gault formula) treated with cisplatin. PPK analysis was performed by nonlinear mixed effect modeling using NONMEM (Version 7.2). We evaluated gender, age, body surface area (BSA), weight, baseline Ccr, baseline serum creatinine (Scr), and baseline urea nitrogen as potential covariates. The final model was evaluated using bootstrap analysis. Renal toxicity was evaluated using Common Terminology Criteria for Adverse Events ver. 4.0. The frequency of severe renal dysfunction (Grade 3/4 Scr elevation) was measured in the population. RESULTS: A one-compartment model adequately described the unchanged cisplatin data. The population mean values for clearance (CLtot) and volume of distribution (Vd) were 19.1 L/h [coefficient of variation (CV) 19.4%] and 13.8 L (CV 41.0%), respectively. The final model identified BSA as a significant covariate for CLtot. There were no significant covariates for Vd. No patients suffered from severe nephrotoxicity to the point that hemodialysis was required. CONCLUSION: Moderate renal dysfunction does not affect the PKs of unchanged cisplatin. The increased serum concentration of cisplatin may not lead to increased toxicity in patients with renal dysfunction. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: UMIN000007091 (January 17, 2012).
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Lesión Renal Aguda/epidemiología , Cisplatino/farmacocinética , Neoplasias/tratamiento farmacológico , Eliminación Renal/fisiología , Insuficiencia Renal/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/fisiopatología , Anciano , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Creatinina/sangre , Creatinina/metabolismo , Creatinina/orina , Conjuntos de Datos como Asunto , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Neoplasias/sangre , Neoplasias/complicaciones , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/etiología , Insuficiencia Renal/fisiopatología , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
The focus of the review is on roles of autophagy and pancreatic secretory trypsin inhibitor (PSTI), an endogenous trypsin inhibitor, in trypsinogen activation in acute pancreatitis. Acute pancreatitis is a disease in which tissues in and around the pancreas are autodigested by pancreatic digestive enzymes. This reaction is triggered by the intrapancreatic activation of trypsinogen. Autophagy causes trypsinogen and cathepsin B, a trypsinogen activator, to colocalize within the autolysosomes. Consequently, if the resultant trypsin activity exceeds the inhibitory activity of PSTI, the pancreatic digestive enzymes are activated, and they cause autodigestion of the acinar cells. Thus, autophagy and PSTI play important roles in the development and suppression of acute pancreatitis, respectively.
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Autofagia/fisiología , Pancreatitis/metabolismo , Inhibidor de Tripsina Pancreática de Kazal/fisiología , Tripsinógeno/metabolismo , Células Acinares/patología , Animales , Catepsina B/metabolismo , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Activación Enzimática , Glicoproteínas/deficiencia , Humanos , Lisosomas/enzimología , Ratones , Ratones Noqueados , Chaperonas Moleculares/fisiología , Pancreatitis/enzimología , Pancreatitis/patología , Proteínas de Secreción Prostática , Pliegue de Proteína , Proteolisis , Vesículas Secretoras/enzimología , Factor de Transcripción CHOP/deficiencia , Inhibidor de Tripsina Pancreática de Kazal/deficienciaRESUMEN
Mesenteric defects are often not closed in laparoscopic colectomy. We herein report a case of an internal hernia projecting through a mesenteric defect following laparoscopy-assisted right hemicolectomy. A 74-year-old woman was hospitalized for the surgical treatment of double colon cancer. Preoperative colonoscopy demonstrated the presence of ascending colon and transverse colon cancers. A laparoscopic-assisted right hemicolectomy was performed. The mesenteric defect resulting from the colectomy was not closed. Three months after the surgery, the patient developed a bowel obstruction. Under a diagnosis of strangulated bowel obstruction, we performed a laparotomy, and found a necrotic small bowel, which had passed into the bursa omentalis through the mesenteric defect. We removed the necrotic small bowel and closed the mesenteric defect by suturing. The patient's postoperative course was uneventful. An internal hernia projecting through a mesenteric defect following laparoscopy-assisted right hemicolectomy developed a severe strangulated bowel obstruction.
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INTRODUCTION: In a distal pancreatectomy combined with a distal gastrectomy, the splenic artery and vein must be conserved. However, it is not easy in pure laparoscopic surgery. We performed a hand-assisted laparoscopic spleen-preserving distal pancreatectomy (HALS-SPDP) combined with a laparoscopic distal gastrectomy (LDG) for the treatment of a pancreatic neuroendocrine tumor (NET) with early gastric cancer. PRESENTATION OF CASE: A 67-year-old male was hospitalized with no complaint. He was diagnosed with a pancreatic tail tumor (1.5cm in diameter) and early gastric cancer. He had undergone an endoscopic submucosal dissection (ESD). The pathohistology of the dissected tissue demonstrated that the histology was moderately differentiated adenocarcinoma, and the depth of the gastric cancer was pT1b2 (submucosal layer â¼1000µm). First, a pancreatectomy was performed extracorporeally under direct vision after detaching the spleen and the distal pancreas from the retroperitoneum under a hand-assisted laparoscopy. After the distal pancreatectomy, an LDG with a D1 lymphadenectomy was performed intracorporeally. The postoperative course was not eventful. Six months after surgery, an enhanced computed tomography (CT) scan revealed the patency of the splenic artery. CONCLUSION: An HALS-SPDP combined with an LDG is beneficial and safe for the patients who have a pancreatic benign or low-grade malignant tumor and gastric cancer.
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BACKGROUND: To date, the optimal surgical strategy for remnant gastric cancer has not been determined. The purpose of this study was to clarify the significance of lymphadenectomy with splenectomy in remnant gastric cancer surgery. METHODS: This retrospective cohort study was conducted at the Kumamoto Regional Medical Center. The primary endpoint was overall survival after surgery. We retrospectively analyzed the clinicopathologic features, surgical treatments, and long-term prognosis of remnant gastric cancer patients treated with total gastrectomy. RESULTS: A total of 80 patients with gastric cancer in the remnant stomach after distal gastrectomy and who underwent total gastrectomy were enrolled in the study. Splenectomy was performed in 38 patients. Lymph node metastasis in the splenic hilum was not observed in the patients with pT1/pT2 tumors, whereas nodal metastasis at the splenic hilum was detected in 30.4% of the patients with pT3/pT4 tumors. The survival rate of the patients with pT3/pT4 tumors who underwent splenectomy was significantly higher than that of the patients who did not undergo splenectomy, although there was no difference in the patients with pT1/pT2 tumors. Among the patients classified as R0, the survival rate of the patients with pT3/pT4 tumors who underwent splenectomy was significantly higher than that of the patients who did not undergo splenectomy. CONCLUSION: Lymphadenectomy with splenectomy in radical surgery is beneficial for patients with advanced (pT3/pT4) remnant gastric cancer.
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Adenocarcinoma Mucinoso/cirugía , Adenocarcinoma/cirugía , Carcinoma de Células en Anillo de Sello/cirugía , Gastrectomía , Escisión del Ganglio Linfático , Esplenectomía , Neoplasias Gástricas/cirugía , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células en Anillo de Sello/mortalidad , Carcinoma de Células en Anillo de Sello/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de SupervivenciaRESUMEN
BACKGROUND: The mortality rate of patients complicated with sepsis-associated organ failure remains high in spite of intensive care treatment. The purpose of this study was to define the duration of systemic inflammatory response syndrome (SIRS) before organ failure (DSOF) and determine the value of DSOF as a prognostic factor in septic patients. METHODS: This retrospective cohort study was conducted in an 11-bed medical and surgical intensive care unit (ICU) in a university hospital. The primary endpoint was in-hospital mortality of the septic patients. RESULTS: One hundred ten septic patients with organ failure and/or shock were enrolled in this study. The in-hospital mortality rate was 36.9%. The median DSOF was 28.5 h. As a metric variable, DSOF was a statistically significant prognostic factor according to univariate analysis (survivor: 74.7 ± 9.6 h, non-survivor: 58.8 ± 16.5 h, p = 0.015). On the basis of the ROC curve, we defined an optimal cutoff of 24 h, with which we divided the patients as follows: group 1 (n = 50) comprised patients with a DSOF ≤24 h, and group 2 (n = 60) contained patients with a DSOF >24 h. There were statistically significant differences in the in-hospital mortality rate between the two groups (52.0% vs. 25.0%, p = 0.004). Furthermore, by multivariate analysis, DSOF ≤24 h (odds ratio: 5.89, 95% confidence interval: 1.46-23.8, p = 0.013) was a significant independent prognostic factor. CONCLUSION: DSOF may be a useful prognostic factor for severe sepsis.
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Burn injury is associated with inflammatory responses and metabolic alterations including insulin resistance. Impaired insulin receptor substrate-1 (IRS-1)-mediated insulin signal transduction is a major component of insulin resistance in skeletal muscle following burn injury. To further investigate molecular mechanisms that underlie burn injury-induced insulin resistance, we study a role of inducible nitric oxide synthase (iNOS), a major mediator of inflammation, on burn-induced muscle insulin resistance in iNOS-deficient mice. Full-thickness third-degree burn injury comprising 12% of total body surface area was produced in wild-type and iNOS-deficient C57BL/6 mice. Insulin-stimulated activation (phosphorylation) of IR, IRS-1, and Akt was assessed by immunoblotting and immunoprecipitation. Insulin-stimulated glucose uptake by skeletal muscle was evaluated ex vivo. Burn injury caused induction of iNOS in skeletal muscle of wild-type mice. The increase of iNOS expression paralleled the increase of insulin resistance, as evidenced by decreased tyrosine phosphorylation of IR and IRS-1, IRS-1 expression, insulin-stimulated activation of phosphatidylinositol 3-kinase and Akt/PKB, and insulin-stimulated glucose uptake in mouse skeletal muscle. The absence of iNOS in genetically engineered mice significantly lessened burn injury-induced insulin resistance in skeletal muscle. In wild-type mice, insulin tolerance test revealed whole-body insulin resistance in burned mice compared with sham-burned controls. This effect was reversed by iNOS deficiency. Unexpectedly, however, blood glucose levels were depressed in both wild-type and iNOS-deficient mice after burn injury. Gene disruption of iNOS ameliorated the effect of burn on IRS-1-mediated insulin signaling in skeletal muscle of mice. These findings indicate that iNOS plays a significant role in burn injury-induced skeletal muscle insulin resistance.
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Glucemia/metabolismo , Quemaduras/metabolismo , Resistencia a la Insulina/fisiología , Músculo Esquelético/metabolismo , Óxido Nítrico Sintasa de Tipo II/deficiencia , Óxido Nítrico Sintasa de Tipo II/metabolismo , Animales , Quemaduras/sangre , Quemaduras/fisiopatología , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Insulina/metabolismo , Transducción de Señal , Tirosina/metabolismoRESUMEN
Nitric oxide (NO) shows tumoricidal activity. We had previously reported that NO downregulates the phosphatidylinositol-3-kinase/Akt pathway, but upregulates the MEK/ERK pathway downstream of growth factor signaling. We hypothesized that NO donor and MEK inhibitor in combination synergistically inhibit the viability of cancer cells compared to either NO donor or MEK inhibitor alone. We determined the effects of S-nitrosoglutathione (GSNO, NO-donor) and U0126 (MEK inhibitor) on insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) signaling, proliferation and invasion in cancer cell lines. GSNO inhibits phosphorylation of IGF-I receptor (IGF-IR), EGF receptor (EGFR) and Akt, but upregulates ERK1/2 phosphorylation in MIAPaCa-2 and HCT-116 cells after stimulation by IGF-I and EGF. On the other hand, U0126 inhibits phosphorylation of ERK1/2, but upregulates phosphorylation of IGF-IR and EGFR in MIAPaCa-2 and HCT-116 cells. The combination of GSNO and U0126 downregulates phosphorylation of IGF-IR, EGFR, Akt and ERK1/2 after stimulation by IGF-I and EGF. GSNO as well as U0126, inhibits the proliferation of MIAPaCa-2, HCT-116, Panc-1, MCF-7, HT-29 and AGS cells in a dose-dependent manner. GSNO and U0126 in combination synergistically inhibit proliferation and invasion of cancer cells. These results indicate that the combined treatment of NO donor and MEK inhibitor may be promising in cancer therapy.
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Butadienos/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Donantes de Óxido Nítrico/farmacología , Nitrilos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Células HCT116 , Células HT29 , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Invasividad Neoplásica , Óxido Nítrico/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , S-Nitrosoglutatión/farmacología , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
A 57-year-old man was admitted to our hospital with a complaint of perineal pain. He was diagnosed as advanced rectal cancer with an invasion of prostate, and we conducted neoadjuvant capecitabine, oxaliplatin, bevacizumab and radiation therapy. After chemoradiation therapy, the tumor regressed to an ulcerative lesion without invasion of the prostate. Abdominoperineal resection was then performed without radical resection. The tumor regressed to an ulcer and only a few cancer cells were detected in the submucosal layer pathologically.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Terapia Neoadyuvante , Compuestos Organoplatinos/uso terapéutico , Neoplasias del Recto/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Bevacizumab , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias del Recto/patología , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Tomografía Computarizada por Rayos XRESUMEN
A 67-year-old man underwent right hemi-colectomy for ascending colon cancer in 2007. One year later, he was diagnosed as early gastric cancer, and endoscopic submucosal dissection was performed. Pathologically, cancer cells were detected on the vertical margin, so we conducted distal gastrectomy. A dissected lymph node around the hepatic artery was histologically proved to contain adenocarcinoma cells. The cancer cells were positive for CK20. Colon cancer cells were also positive for CK20 but gastric cancer cells were focally positive for CK20. This pattern of CK staining suggested the ascending colon cancer metastasized to a gastric regional lymph node.
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Colon Ascendente/patología , Neoplasias del Colon/patología , Escisión del Ganglio Linfático , Neoplasias Gástricas/cirugía , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Humanos , Metástasis Linfática , Masculino , Estadificación de Neoplasias , Inducción de Remisión , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/secundarioRESUMEN
Nitric oxide (NO), which plays a role in the posttranslational modification of proteins, exhibits tumoricidal activity. However, the mechanism remains largely unclear. We investigated whether the regulation of insulin receptor substrate (IRS)-1 protein expression and insulin/insulin-like growth factor (IGF) signaling by NO is involved in the proliferation and invasion of pancreatic cancer cells. NO donor inhibited insulin/IGF-I-stimulated phosphorylation of insulin receptor/IGF-I receptor, IRS-1, Akt/PKB, and glycogen synthase kinase-3beta along with decreased expression of IRS-1 protein in MIAPaCa-2 cells, whereas NO donor enhanced the phosphorylation of extracellular signal-regulated kinase-1/2. In contrast, a selective inducible nitric oxide synthase inhibitor, 1400W, upregulated the expression of IRS-1 protein and the phosphorylation of IRS-1, Akt/PKB, and glycogen synthase kinase-3beta, along with enhanced proliferation and invasion of Panc-1 cells expressing inducible nitric oxide synthase protein. NO donor induced IRS-1 protein reduction through increased ubiquitination and degradation. For the detection of the site responsible for NO-induced ubiquitination, IRS-1 deletion mutant genes were transfected and overexpressed in MIAPaCa-2 cells. The results indicate that the COOH terminus of the IRS-1 protein is required for NO donor-induced ubiquitination and protein degradation. Cells stably transfected with COOH-terminal deletion mutants of IRS-1 exhibited reduced IGF signaling and cell proliferation compared with vector alone-transfected cells, with no influence of NO on IGF signaling and invasion, although stable transfectants with full-length IRS-1 protein exhibited remarkable NO-induced reduction in IGF signaling, cell proliferation, and invasion. These findings indicate that NO inhibits the proliferation and invasion of pancreatic cancer cells, at least in part, through upregulation of IRS-1 protein degradation and resultant downregulation of the insulin/IGF-I-Akt pathway.
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Movimiento Celular , Proliferación Celular/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Óxido Nítrico/farmacología , Neoplasias Pancreáticas/prevención & control , Ubiquitina/metabolismo , Western Blotting , Adhesión Celular , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Inmunoprecipitación , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/metabolismo , Invasividad Neoplásica , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Células Tumorales Cultivadas , UbiquitinaciónRESUMEN
AIM: The changes in the serum hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta1 levels after portal vein embolization (PVE), and their clinical significance, remain unclear and we aimed to assess their relationship. METHODS: The serum HGF and TGF-beta1 levels were prospectively measured in 22 patients before and 1, 3, 5, 7, and 14 day after right PVE. Computed tomographic volumetry was performed before and at a mean of 26 +/- 4 days after right PVE. RESULTS: Three to four weeks after right PVE, the volume of embolized lobe significantly decreased from 704 +/- 157 cm(3) before PVE to 539 +/- 168 cm(3) after PVE (P < 0.001). In contrast, the volume of nonembolized lobe significantly increased from 426 +/- 142 cm(3) to 560 +/- 165 cm(3) (P < 0.001). The serum HGF level significantly increased on day 3 after PVE compared with the pretreatment level (P = 0.005), while the serum TGF-beta1 level significantly decreased and reached its lowest value on day 3 (P = 0.002). Using Pearson's correlation analysis, we found that the serum HGF and TGF-beta1 levels on day 14 negatively associated with the large hypertrophic response in the nonembolized lobe (HGF: r = -0.490, P = 0.021; TGF-beta1: r = -0.473, P = 0.026). CONCLUSIONS: PVE induced an increase in the serum HGF level and reduced the serum TGF-beta1 level. Measurement of serum HGF and TGF-beta1 levels on day 14 after right PVE may be useful for assessment of the future liver hypertrophy in nonembolized lobe after right PVE.